The development of resistance to antiparasitic drugs, such as ivermectin, poses a significant challenge for the agricultural industry and global human health. It is imperative to enhance the efficacy of existing drugs by identifying new targets against resistance. Among various resistance mechanisms, highly conserved nuclear receptors in nematodes play a role in biocide resistance by regulating the expression of genes in drug detoxification systems. We have demonstrated that the NHR-8 receptor in nematodes, which regulates lipid homeostasis, also influences the tolerance and the development of resistance to ivermectin. The strategic importance of this receptor makes it a pertinent target for combating pathogens and enhancing the effectiveness of existing drugs. We possess several original strains of the parasitic nematode model Caenorhabditis elegans invalidated for NHR-8. Using an RNA-seq transcriptomic approach, we confirmed the involvement of NHR-8 in regulating genes related to stress response, detoxification, and metabolism in the context of ivermectin-resistant or wild-type strains. In addition to underscoring the significance of NHR-8 in ivermectin resistance, this work will contribute to our understanding of the complex transcriptomic regulation controlled by the still poorly understood NHR-8 receptor.